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PubMed1988

Chronic morphine treatment increases cyclic AMP-dependent protein kinase activity in the rat locus coeruleus.

We have studied a possible role for cyclic AMP-dependent protein kinase in mediating opiate addiction in the central nervous system by focusing on the rat locus coeruleus. This brain region is well suited for these studies because it is relatively homogeneous and because a wealth of electrophysiological and behavioral data indicate that it plays an important role in mediating the chronic effects of opiates in animals, including humans. It was found that chronic, but not acute, in vivo treatment of rats with morphine increased cyclic AMP-dependent protein kinase activity in the locus coeruleus with a time course that closely paralleled the time course by which locus coeruleus neurons become tolerant to and dependent on opiates, based on electrophysiological studies. Concomitant administration of the opiate receptor antagonist naltrexone was found to block the effect of chronic morphine treatment on protein kinase activity, indicating that the effect is mediated via specific activation of opiate receptors. In contrast, chronic morphine treatment did not alter protein kinase activity in several other brain regions studied, including the neostriatum, frontal cortex, and dorsal raphe. We propose that the observed increase in cyclic AMP-dependent protein kinase activity in the locus coeruleus contributes to the biochemical basis of opiate addiction.

Animals↗
PubMed2001

Determination of tetrahydrobiopterin in murine locus coeruleus by HPLC with fluorescence detection.

Tetrahydrobiopterin in the murine locus coeruleus was measured as its fully oxidized form, biopterin, using a HPLC coupled to a fluorescence detector, because tetrahydrobiopterin itself cannot be detected by such means. The differential oxidization method distinguished tetrahydrobiopterin-derived biopterin and dihydrobiopterin-derived biopterin. The protocol reported here is a rapid and sensitive method that facilitates the measurement of tissue and/or cellular tetrahydrobiopterin. Using this assay protocol, we were able to detect and quantify variations in the tetrahydrobiopterin content in the murine locus coeruleus.

Animals↗
PubMed1980

Genetic studies of daily variations of first-step enzymes of monoamines metabolism in the brain of inbred strains of mice and hybrids. II. Daily variations of tyrosine hydroxylase activity in the locus coeruleus.

Daily variations of tyrosine hydroxylase (TH) activity in the locus coeruleus of 3 inbred strains of mice (BALB/c; C57BL6; C57Br) and the F1 hybrids obtained from BALB/c and C57BL/6 are discussed. Precise characteristics of the circadian rhythms were observed in each strain. They were found significantly different in two genetically pure parents (BALB/c and C57BL6). In their two F1 hybrids the daily variation of TH activity was similar to that observed in one of the parents (C57BL6). This strongly suggests selective and genetically controlled mechanisms of regulation responsible for the daily variation of TH activity in the locus coeruleus of mice.

Animals↗
PubMed1984

Lesions of the locus coeruleus abolish baroreceptor-induced depression of supraoptic neurones in the rat.

Urethane-anaesthetized rats were used to investigate the influence of lesions within the locus coeruleus on the inhibition of phasically discharging supraoptic neurones that normally follows the activation of arterial baroreceptors. Carotid sinus baroreceptors were stimulated by the inflation of a blind sac of the carotid bifurcation. A general activation of arterial baroreceptors was evoked by increasing arterial blood pressure following the intravenous injection of the pure alpha-adrenoreceptor agonist phenylephrine. The locus coeruleus of one side only was destroyed either by thermal (radio-frequency) lesions, or by the injection of 6-hydroxydopamine (1 microliter, 0.5 mg/ml). The extent of each lesion was assessed histologically in stained tissue and with fluorescence histochemistry. Lesions in locus coeruleus abolished all baroreceptor input to supraoptic neurones on the side ipsilateral to the lesion. The lesions had no effect on the cardiovascular responses to the stimulus, and did not abolish the excitation of supraoptic neurones after ipsilateral carotid body chemoreceptor activation. 6-Hydroxydopamine lesions (1 microliter, mg/ml) in the rostral part of the ventrolateral A1 catecholamine neurones were less consistent in their abolition of baroreceptor input to the supraoptic nucleus. When the input from ipsilateral carotid sinus baroreceptors was abolished, there was an equivalent effect on the influence of the carotid body chemoreceptors. Input from other arterial baroreceptors, activated by phenylephrine injection, was not affected. From these results, it is proposed that the baroreceptor-induced depression of-phasically discharging supraoptic neurones is mediated via a direct noradrenergic input from the locus coeruleus.

Action Potentials↗
PubMed2001

Morphine withdrawal increases expression of GABA(A) receptor epsilon subunit mRNA in locus coeruleus neurons.

An increase in the activity of brain stem locus coeruleus noradrenergic neurons has been hypothesised to be a major factor accounting for opiate withdrawal symptoms. These neurons are under GABAergic inhibition. Their GABA(A) receptors have unique pharmacological properties, most likely due to the enriched expression of GABA(A) receptor subtypes containing novel epsilon and straight theta subunits. Using in situ hybridisation of cryostat sections, we now report a significant increase in the epsilon subunit mRNA expression after precipitation of opioid withdrawal by naloxone. Similar changes were detected in tyrosine hydroxylase mRNA expression. The results suggest increased formation of unique GABA(A) receptor subtype(s) in the locus coeruleus neurons during increased neuronal activity.

Animals↗
PubMed1977

The effect of lesions in the locus coeruleus on the physiological responses of the cerebral blood vessels in cats.

The effects of cerebral blood flow (CBF) of lesions placed stereotactically in or near the locus coeruleus were studied in 15 lightly anesthetized cats; 5 control cats in which the electrode was placed but no lesion created, and 10 experimental cats in which a lesion was created. The response of CBF to changes in Paco2 and in mean arterial blood pressure was determined by 133Xe-washout studies 10 days after the stereotactic procedures. The sites of the lesions were studied histologically, and their effects on catecholamine concentrations in the paraventricular hypothalamic nucleus, anterior ventral nucleus of the thalamus, and parietal cortex were determined by radio-chemical assay. Control animals and those with lesions near, but not in, the locus coeruleus had normal Paco2--CBF response curves and normal catecholamine concentrations in the areas of biopsy. Bilateral destruction of the locus coeruleus was confirmed in 3 animals on histological examination and in these animals there were decreased levels of catecholamines in the areas of assay, higher resting CBFs at normocapnia, and significantly abnormal CBF--Paco2 response curves. The autoregulatory response to changes in perfusion pressure was preserved. Thus, noradrenergic neurons originating in the locus coeruleus may contribute to the control of intraparenchymal cerebral vessels and disturbance of this control may be important in the pathology of cerebral ischemia.

Animals↗
PubMed1986

Delayed up-regulation of alpha-adrenoceptor populations in particular regions of the rat brain after stimulation of the nucleus locus coeruleus.

We previously showed that electrical stimulation of the nucleus locus coeruleus resulted 4 weeks later in greatly improved performance in the acquisition and extinction of a food-reinforced operant task. To ascertain whether adrenergic receptors of particular brain regions were involved in this long term behavioral modification, we studied the characteristics of alpha 1, and alpha 2 and beta-binding sites after stimulation of the locus coeruleus. In the first experiment these characteristics were studied, 4 weeks after treatment, in cortex, hippocampus, hypothalamus and the brainstem. Neither the number, nor the affinity of beta-receptors ([125I]iodocyanopindolol binding sites) was modified in any brain region. A significant increase in the number of alpha 1-receptors ([3H]prazosin binding sites) was observed in the cortex (62%). The number of alpha 2-receptors, ([3H]yohimbine binding sites), was significantly increased in cortex (99%), hippocampus (33%) and hypothalamus (113%). No significant alteration of the alpha 1, alpha 2 and beta-adrenoceptors was observed in the brainstem. To investigate the time course of these adrenoceptor changes, the characteristics of alpha 1, alpha 2 and beta-adrenoceptors were studied 2 weeks after stimulation using the same ligands and in the same brain regions. The only significant modifications observed were an increase of the alpha 2-adrenoceptors in the cortex (19.4%) and in the hypothalamus (54%). Furthermore, in both experiments, the increase in the number of alpha 1 and alpha 2-receptors was associated with a significant decrease in affinity. These results are discussed in relation to our previous behavioral and pharmacological findings.

Animals↗
PubMed1981

Modulation of rat brain alpha-adrenoreceptor populations four weeks after stimulation of the nucleus locus coeruleus.

We previously showed that electrical stimulation of the nucleus locus coeruleus was followed 4 weeks later by a greatly improved performance in the acquisition of a food-reinforced operant task. To ascertain whether adrenergic receptors were involved in this long-term behavioral modification, we studied the characteristics of the alpha 1, alpha 2, and beta-adrenoreceptors of the cerebral cortex 4 weeks after stimulation of the locus coeruleus. This stimulation induced a slight (14%) but significant increase in the number of alpha 1-receptor [(3H) WB 4101 binding sites] as well a rise in the number of alpha 2-receptor [(3H) clonidine binding sites]. The latter rise mainly affected high-affinity alpha 2-receptor sites (36%) and the number of low-affinity sites remained unchanged. No significant alteration in the number of beta-receptors [(3H)-dihydroalprenolol binding sites] was observed. To confirm this biochemical result, the effect of very small doses of clonidine (1, 2.5, 5 and 10 micrograms/kg) was tested on locomotor activity in the open-field. In rats stimulated 4 weeks before injection, clonidine induced a biphasic effect, comprising firstly sedation which occurred 30 min after injection, and secondly, long-term hyperactivity which began 24 h injection. For the 5 micrograms/kg dose, this rebound of activity was detectable 8 days after injection. In implanted, control rats, only the sedative effect was observed. These findings are interpreted in relation to the current theories about alpha-adrenoreceptors.

Animals↗
PubMed2006

Ovarian steroids but not the locus coeruleus regulate stress-induced prolactin secretion in female rats.

Stress has been proposed to stimulate prolactin release if its prestress levels are low, or to inhibit it if they are elevated, but the role of ovarian-steroid fluctuations in the prolactin stress response is not yet clearly understood. Because the noradrenergic nucleus locus coeruleus has been implicated in stress responses and generation of prolactin surges in female rats, the present study aimed to evaluate stress-induced prolactin secretion under different hormonal conditions, determining the effect of locus coeruleus lesion on each response. Blood samples were withdrawn from a jugular vein catheter 5 and 2 min before and 2, 5, 10, 15 and 30 min after ether stress in male rats, female rats during the oestrous cycle and ovariectomised rats treated with oil (OVX), oestradiol (OVE) or oestradiol plus progesterone (OVEP). Increased Fos immunoreactivity demonstrated locus coeruleus activation following ether stress. Ether stress increased both low (at 16.00 h in males, in OVX and on dioestrous and at 11.00 h on pro-oestrous and oestrous) and high plasma prolactin (at 16.00 h on oestrous and in OVE), but it decreased elevated prolactin levels during the afternoon on pro-oestrous and in OVEP. Locus coeruleus lesion prevented prolactin surges during the afternoon on pro-oestrous, oestrous, OVE and OVEP but did not modify either pattern (i.e. increase or decrease) or degree of prolactin stress response under any condition studied. The present data therefore suggest that oestradiol and progesterone modulate stress-induced prolactin secretion, regardless of its prestress levels. Moreover, the locus coeruleus is probably not involved in prolactin response to stress and most likely has a specific role in prolactin surges induced by ovarian steroids.

Analysis of Variance↗
PubMed1987

Behavioural, biochemical and histochemical effects of locus coeruleus transplantation in rats with neurotoxic lesions of the catecholaminergic system.

Exploratory activity in the open field and noradrenaline concentration in the neocortex and brain stem were investigated in intact rats (n = 10) and in the following groups of rats with early postnatal neurotoxic (6-hydroxydopamine) lesion of the catecholaminergic system: (i) rats with embryonal locus coeruleus grafts in the frontal neocortex (n = 5); (ii) rats with the same grafts in lateral ventricles (n = 4); (iii) a control group with intracortical hippocampal tissue grafts (n = 3); (iv) sham-operated rats (n = 3). Experiments were performed by four independent groups of investigators using a double-blind method. In sham-operated rats as well as in rats with hippocampal grafts, and with locus coeruleus grafts in the ventricles, both exploratory activity and noradrenaline content of the forebrain were significantly lowered. In the rats with intracortical locus coeruleus grafts the level of exploratory activity was much higher (almost as in intact controls). This improvement of exploratory behaviour correlated highly with increased noradrenaline concentration in the forebrain. In all animals with locus coeruleus in lateral ventricles a significant increase in noradrenaline level of the brain stem was present, but no change of exploratory behaviour was observed. The grafts with the 3-mm-thick slabs of the adjacent tissue were dissected from the brain and used for histological analysis. The presence of typical locus coeruleus cells was shown in neocortex of all animals which received the grafts of corresponding tissue. The data show the possibility of stable compensation of the forebrain noradrenaline level and exploratory behaviour by embryonic noradrenergic neurons grafted into the neocortex, but not into lateral ventricles.

Animals↗
PubMed1983

Effects of locus coeruleus stimulation on carotid vascular resistance in the cat.

The locus coeruleus was stimulated in 62 cats in order to investigate the effect on cephalic blood flow and cephalic vascular resistance. Flow was measured by electromagnetic flow probes applied to the common carotid artery. Stimulation over a range of frequencies (0.2-200 s-1) produced a frequency-dependent fall in carotid vascular resistance, greater on the ipsilateral side. This response was not affected by either cervical sympathectomy or spinal cord section. The response was blocked by bilateral section of the facial nerve but was not abolished by classical cholinergic, histaminergic or adrenergic blocking agents. Stimulation of the locus coeruleus also resulted in a pressor response through spinal mechanisms in which coeruleo-hypothalamic projections were not involved. A post-stimulation constriction in the carotid vasculature followed the dilator response and was attributed to release of catecholamines from the adrenal medulla.

Animals↗
PubMed1999

Spinal action of ketorolac, S(+)- and R(-)-ibuprofen on non-noxious activation of the catechol oxidation in the rat locus coeruleus: evidence for a central role of prostaglandins in the strychnine model of allodynia.

BACKGROUND: Blockade of spinal glycine receptors with intrathecal strychnine produces an allodynia-like state in the anesthetized rat. Innocuous hair deflection in the presence of intrathecal strychnine induces a nociceptive-like activation of catechol oxidation in the locus coeruleus and enhances cardiovascular responses. Because prostaglandins play a central role in augmenting pain, this study evaluated the effect of intrathecal nonsteroidal antiinflammatory drugs in strychnine-induced allodynia. METHODS: In urethane-anesthetized rats, changes in catechol oxidation in the locus coeruleus, measured using in vivo voltammetry, and cardiovascular parameters evoked by hair deflection of caudal dermatomes were determined after strychnine (40 microg) or saline were administered intrathecally. Subsequently, the effects of 30 microg ketorolac, 10 microg S(+)-ibuprofen, and 10 microg R(-)-ibuprofen administered intrathecally were evaluated. RESULTS: After strychnine was administered intrathecally, hair deflection evoked an increase in the locus coeruleus catechol oxidation (peak, 149.7+/-7.2% of baseline) and mean arterial blood pressure (peak, 127.5+/-3.8% of baseline). These responses were not observed after saline was administered intrathecally. All hair deflection-evoked, strychnine-dependent peak responses were attenuated significantly with intrathecally administered ketorolac and S(+)-ibuprofen but not with R(-)-ibuprofen. CONCLUSIONS: Locus coeruleus catechol oxidation is a sensitive biochemical index of strychnine-induced allodynia and is correlated temporally with the cardiovascular responses evoked by hair deflection during spinal glycinergic inhibition. The ability of intrathecally administered ketorolac and S(+)-ibuprofen, but not R(-)-ibuprofen, to suppress the locus coeruleus catechol oxidation and cardiovascular peak responses evoked during strychnine-induced allodynia provide evidence that central prostaglandins play an important role in the abnormal sensory processing of strychnine-induced allodynia.

Anesthesia↗
PubMed1992

Anatomical evidence for genetic differences in the innervation of the rat spinal cord by noradrenergic locus coeruleus neurons.

Pontospinal noradrenergic neurons located in the A5, A6 (locus coeruleus, LC), and A7 cell groups are the major source of the noradrenergic innervation of the spinal cord. We have recently examined the specific terminations of these three cell groups in the spinal cord and found that the LC provides the major noradrenergic innervation of the ventral horn, while the A7 and A5 cell groups innervate the dorsal horn and intermediate zone, respectively. However, the results of similar experiments from another laboratory have shown that noradrenergic neurons in the locus coeruleus primarily innervate the dorsal horn, while the A5 and A7 innervate the intermediate zone and the ventral horn. These conflicting results may be due to fundamental genetic differences between the rats used in our experiments (Sasco Sprague-Dawley) and those used by the other laboratory (Harlan Sprague-Dawley). This possibility was examined by determining the projections of coeruleospinal neurons in these two rat substrains using the anterograde tracer Phaseolus vulgaris leucoagglutinin. The results indicate that in Sasco rats the LC neurons project through the ipsilateral ventromedial funiculus and terminate almost exclusively in the medial part of laminae VII and VIII, the motoneuron pool of lamina IX, and lamina X. In contrast, LC neurons in Harlan rats project bilaterally through the superficial dorsal horn and the dorsolateral funiculus and terminate most heavily in dorsal horn laminae I-IV. In addition, the LC neurons of Sasco rats innervate cervical spinal cord segments more densely than lumbar spinal cord segments, while in Harlan rats the lumbar spinal cord is more densely innervated than the cervical spinal cord. These results indicate that the projections of coeruleospinal neurons in Sasco rats are fundamentally different from those in Harlan rats and suggest that noradrenergic LC neurons may have different physiological functions in these two rat substrains.

Animals↗
PubMed1982

Dopamine-beta-hydroxylase activity in the locus coeruleus and hypothalamus in cold-stressed rats.

Dopamine-beta-hydroxylase (DBH) activity was determined in the locus coeruleus, anterior hypothalamus and posterior hypothalamus of cold-stressed rats. In the acute cold stress, rats were exposed to an ambient temperature of 5 degrees C in a cold room for 5-20 min. In the chronic cold stress, rats were exposed to the same cold temperature for 4 hr once every day in the morning for periods ranging from 1 to 3 weeks. There was decreased DBH activity in the locus coeruleus following acute cold stress and increased activity in both the locus coeruleus and the anterior hypothalamus following the chronically repeated cold stress.

Animals↗
PubMed1980

[Modification of chemoreactive properties of neurons in the neocortex and hippocampus under the effect of electric stimulation of locus coeruleus].

Based on the findings of alterations in the chemoreactivity of neurons under conditioning and its possible significance for the formation of transient neuronal junctions, the authors investigated the influence of electrical stimulation of the Locus coeruleus upon the transmitter sensitivity of cortical and hippocampal neurons. The majority of neurons showed immediately after stimulation of the Locus coeruleus a different reaction to microiontophoretic application of acetylcholine, dopamine and glutamate than under normal conditions. Obviously there must have occurred qualitative changes because a superposition effect of the reactions following stimulation of the Locus coeruleus and application of the substances has rarely been observed. The release of noradrenaline provoked by the stimulation of the Locus coeruleus evidently leads to qualitative changes in the neurone texture, which may occur both inter- and intraneuronally.

Acetylcholine↗
PubMed2003

Peripheral administration of lipopolysaccharide enhances the expression of guanosine triphosphate cyclohydrolase I mRNA in murine locus coeruleus.

GTP cyclohydrolase I is the first and rate-limiting enzyme for the de novo biosynthesis of tetrahydrobiopterin, which is the cofactor for tyrosine hydroxylase. Lipopolysaccharide can modulate tetrahydrobiopterin production by upregulating GTP cyclohydrolase I protein expression in the locus coeruleus in the mouse brain. The increased supply of tetrahydrobiopterin in the locus coeruleus leads to increased tyrosine hydroxylase activity without affecting the level of tyrosine hydroxylase protein expression, resulting in an increase in norepinephrine turnover at the site. This study was performed to address whether the increase in GTP cyclohydrolase I protein is dependent on the de novo synthesis of GCH in the locus coeruleus. After i.p. administration of lipopolysaccharide, the mRNA expression of GTP cyclohydrolase I was examined. The expression level increased within 2 h, and reached to maximum level at 4 h after the lipopolysaccharide administration. However, the mRNA expression level of 6-pyruvoyl-tetrahydropterin synthase and sepiapterin reductase, both of which are involved successively after GTP cyclohydrolase I in tetrahydrobiopterin biosynthesis, were not affected by the lipopolysaccharide administration. These results suggest that GTP cyclohydrolase I upregulation alone is enough to modulate tetrahydrobiopterin production in the locus coeruleus. In addition, the mRNA level of tyrosine hydroxylase was also not affected by the lipopolysaccharide administration. Taken together, the data indicate that GTP cyclohydrolase I plays a crucial role in regulating norepinephrine biosynthesis by a pathway the activity of which is triggered by lipopolysaccharide i.p. administration.

Alcohol Oxidoreductases↗
PubMed1993

Long-term effect of RU24722 on tyrosine hydroxylase in the rat locus coeruleus: differential effects of two enantiomeric forms.

RU24722, as a racemic mixture, has been found to act on neuronal activity and the long-term regulation of tyrosine hydroxylase in the locus coeruleus of the rat. In this study, the effects of two enantiomeric derivatives of RU24722 (3 alpha and 16 alpha forms), as compared to the racemic form itself, are studied. The short-term effect was estimated 20 min after treatment by measuring variations in 3,4-dihydroxyphenylacetic acid content in the locus coeruleus. The long-term effect was determined by evaluating tyrosine hydroxylase protein concentration in the locus coeruleus 3 days after a single injection. Comparison of actions of both enantiomers showed that the 16 alpha form was 3-fold more potent in eliciting tyrosine hydroxylase protein elevations at three days, whereas the 3 alpha isomer increased 3,4-dihydroxyphenylacetic acid content 2-fold more in the short-term. These results seem to show that the 16 alpha configuration is crucial for the long term regulation of tyrosine hydroxylase protein elicited by RU24722 within the locus coeruleus.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1986

Autotomy after nerve sections in the rat is influenced by tonic descending inhibition from locus coeruleus.

This study examined the role of descending brainstem inhibition on autotomy (self-mutilation) produced by neurectomy, and on the enhancement of autotomy by an injury prior to denervation. Autotomy after sciatic and saphenous nerve sections was examined following lesions of the locus coeruleus (or sham lesions) in rats which were either uninjured or previously injured by an injection of formalin into the hindpaw. The prior injury of the paw produced a significant increase in autotomy which occurred earlier in rats with lesions of the locus coeruleus than in the sham controls. The locus coeruleus lesion by itself also produced an enhancement of autotomy. These results suggest that self-mutilation following neurectomy, and possibly its enhancement by prior injury, are subject to tonic inhibition due to descending controls from the locus coeruleus.

Animals↗